Engineered Dendritic Cell-Derived Vesicles for T-Cell-Targeted Magnesium Delivery and Metabolic Reprogramming.

The tumor microenvironment (TME) fosters immunosuppression and T-cell exhaustion, which limit the efficacy of immunotherapy. Magnesium ions (Mg2+) have recently been identified as potent immunomodulators that enhance cytotoxic T lymphocyte (CD8+ T) activity. However, conventional carriers for Mg2+ delivery suffer from poor biocompatibility and inefficient targeting, restricting therapeutic outcomes. In this study, we developed an engineered extracellular vesicle (EV)-based system for targeted Mg2+ delivery. Dendritic cells were genetically modified to overexpress magnesium-specific channel protein MgtE (SLC41A1), enabling efficient Mg2+ encapsulation into dendritic cell-derived EVs (E-DEVs). The resulting Mg2+-loaded vesicles (E-DEVs@Mg2+) displayed strong tropism toward tumor-draining lymph nodes (TDLNs) and effectively modulated T-cell metabolism. Mechanistic studies revealed that E-DEVs@Mg2+ enhanced glycolysis and oxidative phosphorylation, restoring the metabolic fitness of exhausted CD8+ T cells. When combined with immune checkpoint blockade therapy, this strategy achieved a synergistic tumor suppression. Our findings highlight engineered DEVs as a biocompatible and effective Mg2+ delivery platform, providing a promising approach for metabolic reprogramming and improved cancer immunotherapy.